Sulfur isostere

Bisehler-Napieralski reaetions, 4, 279 carboline synthesis from, 4, 516 Mannieh-type reactions, 4, 279 sulfur isosteres, biological activity, 4, 913 synthesis, 4, 337, 913 Tryptophan... 

Once again, clinical studies reveal a divergence between potency and qualitative effect. No in vitro or animal model studies have yet indicated any major difference between oxygen at the 4-position and its sulfur isostere, although there are changes in their experimentally measured ionization potentials (54). 

G. B. Kok, M. Campbell, B. Mackey, and M. von Itzstein, Synthesis and biological evaluation of sulfur isosteres of the potent influenza vims sialidase inhibitors 4-amino-4-deoxy- and 4-deoxy-4-guanidino-Neu5Ac2en, J. Chem. Soc. Perkin Trans., 1 (1996) 2811-2815. 

With replacement of oxygen by sulfur, and then by selenium, visible absorption is weakened and shifted to longer wavelengths. On the other hand, in the near-ultraviolet region the selenium compound is intermediate between the oxygen and the sulfur isosteres, both with respect to wavelength and intensity of absorption. 

The trans-sulfur isostere (224) of the 3-ace-toxypiperidinium system (222) is weak muscarinic agonist (6-10%as potent as acetylcholine) the cis-isomer (225) is inert (270). 

Other carbohydrate based analogues of zanamivir which have been synthesized as potential influenza virus sialidase inhibitors include the sulfur isostere (37), which was prepared from the known [113] 6-thio-Neu5Ac derivative (38) via a sequence analogous to that shown in Scheme 1.2 for the preparation of zanamivir [114]. The sulphur isostere (37) was found to have comparable activity (IC50 = 5 x 10 9 M) to zanamivir [114]. 

The isosteric relationship of benzene and thiophene has often led medicinal chemists to substitute the sulfur containing heterocycle for benzene drugs in biologically active molecules. That this relationship has some foundation in fact is attested by the observation that the resulting analogs often possess full biologic activity. Alkylation of the diamine, 71 (obtained from aniline and the chloroethylamine), with 2-chloromethylthiophene affords the antihistamine methaphenylene (72) The correspond-... 

The simplest approach to isosteric replacement of one or both sulfur atoms of the cystine disulfide with a methylene or ethylene moiety is given for natural bioactive peptides when one cysteine residue is located in the N-terminal sequence position and the related amino group or peptide extension is not involved in the bioactivity. This allows for direct side chain to backbone (N-terminus) cyclization via amide bonds with suitable 5-carboxyalkyl derivatives of the second cysteine residue, or with the oo-carboxy group of aminodicarboxylic adds containing an alkyl side chain that mimics the Ca to Ca spacer in cystine. Thereby, the length and degree of branching of the sulfide or alkyl spacer can additionally be varied. 

The isostere in which sulfur replaces the methylene group at the 4 position in the furan ring of customary sugars also shows good activity as an inhibitor of HIV reverse transcriptase. The initial step consists of formation of the thioacetal (53-3) from glyoxal benzoate (53-1) and the methyl acetal of thioglyoxal (53-2). Reaction of... 

Monocyclic l,2-dihydro-l,2-azaborines (3) easily form polymers with the exception of the 2-phenyl derivative (109 R = Ph), probably because of interaction between the two rings. In contrast, the alkyl substituted monocyclic system (155) is stable towards polymerization although it is easily oxidized by air and hydrolyzed by water. This stability order between (3) and (155) was predicted by semi-empirical methods. However, the ring system (7), isosteric with pyridine, seems to be the most stable of the monocyclic systems. Some of its alkyl derivatives remain unchanged after 50 h in concentrated sulfuric acid at 80 °C. After reflux in 1M sodium hydroxide almost all of the compound was recovered. 

The chemistry of thienoquinolines has been explored to a limited degree. Two types (378,379) will be described in this subsection. The pharmacological interest in thieno[2,3-Z>]quinoline (378) and derivatives thereof stems from their isosteric and isoelectronic resemblance to acridine furthermore, (378) constitutes the sulfur analog of furoquinoline (Section 3.17.2.1.5), which is the parent system of a number of alkaloids. Thieno[3,4-6]quinoline (379) is an o-quinonoidal heterocycle which is of interest both for theoretical reasons compared with its isoconjugate analogues and as a synthon in Diels-Alder reactions for the preparation of other condensed heterocycles. 

Representatives of all kinds have been explored for synthetic applications while mechanistic investigations were mainly focussed on the distinct FruA enzymes isolated from rabbit muscle [196] and yeast [197,198]. For mechanistic reasons, all DHAP aldolases appear to be highly specific for the donor component DHAP [199], and only a few isosteric replacements of the ester oxygen for sulfur (46), nitrogen (47), or methylene carbon (48) were found to be tolerable in preparative experiments (Fig. 7) [200,201], Earlier assay results [202] that had indicated activity also for a racemic methyl-branched DHAP analog 53 are now considered to be artefactual [203]. Dihydroxyacetone sulfate 50 has been shown to be covalently bound via Schiff base formation, but apparently no a-deprotonation occurred as neither H/D-exchange nor C-C... 

Thiocarbapyranoses are a quite rare compound class in the scenario of pyranoid carbasugars, although replacement of a hydroxyl group with a sulfurized moiety is a classical isosteric modification in medicinal chemistry. 

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